TrialWatch: ArrowHead Pharmaceuticals Files IND for Phase II/III trial of ARO-AAT RNA Interference for Rare Genetic Liver Disease

Arrowhead Pharmaceuticals filed an IND with the FDA for approval to commence an adaptive Phase II/III trial with the potential to serve as a pivotal registrational study of ARO-AAT, the company’s second generation subcutaneously administered RNA interference (RNAi) therapeutic being developed as a treatment for a rare genetic liver disease associated with alpha-1 antitrypsin deficiency (AATD).

The proposed primary objectives are to evaluate safety and pharmacodynamic dose response, and to evaluate efficacy, defined as an improvement in a histologic grading scale of AATD associated liver disease, and no worsening of liver fibrosis based on Ishak score on end of study biopsy. Arrowhead intends to initiate the study at sites across the U.S. in the second quarter of 2019, followed by various international sites in Europe, pending regulatory submission and review. source

About alpha-1 antitrypsin deficiency

AATD is a rare genetic disorder associated with liver disease in children and adults and pulmonary disease in adults. AATD is caused by a genetic mutation. This mutation causes too little or no working alpha-1 antitrypsin protein (AAT) to be made. AAT is made in the liver cells and sent through the bloodstream to the lungs where it helps protect the lungs from damage. Having low levels of AAT, or no AAT, may allow the lungs to become damaged. A build-up of abnormal AAT can cause liver damage.  


ARO-AAT is designed to knock down the hepatic production of the mutant alpha-1 antitrypsin (Z-AAT) protein, the cause of progressive liver disease in AATD patients. Reducing production of the inflammatory Z-AAT protein is expected to halt the progression of liver disease and potentially allow it to regenerate and repair. If approved, ARO-AAT would be the only treatment for liver disease caused by AATD aside from liver transplant.

Concerns over liver toxicity led to Arrowhead Pharmaceuticals discontinuing all of its clinical-stage therapies in November of 2016. This led to the development of a new proprietary subcutaneous (subQ) and extra-hepatic RNA delivery system.